gnptab encodes the alpha/beta precursor of UDP-GlcNAc:lysosomal-enzyme N-acetylglucosamine-1-phosphotransferase (EC 2.7.8.17), a Golgi membrane enzyme that, together with the gamma subunit, transfers GlcNAc-1-phosphate from UDP-GlcNAc onto mannose residues of high-mannose N-glycans on newly synthesised lysosomal hydrolases. This is the first step in generating the mannose 6-phosphate marker that M6P receptors read to sort hydrolases to endolysosomes; the alpha/beta precursor is activated by mbtps1 (S1P) cleavage in the Golgi. Loss of gnptab in zebrafish models mucolipidosis II: hydrolases are hypersecreted into the extracellular space rather than reaching lysosomes, and extracellular cathepsin K activity perturbs TGF-beta-family signalling, producing craniofacial cartilage, bone, otolith, pectoral fin and heart/valve defects.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003976 UDP-N-acetylglucosamine-lysosomal-enzyme N-acetylglucosaminephosphotransferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: GlcNAc-1-phosphotransferase activity (EC 2.7.8.17) inherited from PAINT node PTN002779133; Q3T906 (human GNPTAB) and this zebrafish gene are among the experimental descendants. Reason: The PAINT placement is sound and the zebrafish protein has its own experimental support for the activity: morphant lysates show reduced phosphotransferase activity and loss of mannose phosphorylation of lysosomal glycosidases [PMID:19834066], and wild-type gnptab mRNA rescues hydrolase phosphorylation in the morphant [PMID:23733939]. Core molecular function. Supporting Evidence: file:DANRE/gnptab/gnptab-uniprot.txt EC=2.7.8.17 PMID:19834066 Decreased mannose phosphorylation of several lysosomal glycosidases was observed in morphant lysates, consistent with the reduction in phosphotransferase activity. PMID:23733939 coinjection of WT GlcNAc-1-phosphotransferase mRNA with the morpholino rescued the MLII phenotype and restored Ξ²-galactosidase phosphorylation to levels approaching endogenous levels, whereas the K732N mRNA failed to correct these defects |
| GO:0005794 Golgi apparatus | IBA GO_REF:0000033 | ACCEPT | Summary: Golgi apparatus: the alpha/beta precursor is a Golgi-resident membrane protein (UniProt SUBCELLULAR LOCATION, by similarity to human Q3T906), where it phosphorylates high-mannose N-glycans of lysosomal hydrolases. Reason: PAINT node PTN001171283 places Golgi activity across the family; consistent with the UniProt SUBCELLULAR LOCATION (Golgi apparatus membrane) and with the enzyme acting on Golgi-transiting hydrolases [PMID:26404503]. No zebrafish imaging of the endogenous protein is cached, but the localization is intrinsic to the M6P pathway. Accepted as the core site of action. Supporting Evidence: file:DANRE/gnptab/gnptab-uniprot.txt Golgi apparatus membrane PMID:26404503 The Golgi-localized enzyme UDP-GlcNAc: lysosomal enzyme GlcNAc-1-phosphotransferase initiates the synthesis of M6P tags on the hydrolases. |
| GO:0016256 N-glycan processing to lysosome | IBA GO_REF:0000033 | ACCEPT | Summary: N-glycan processing to lysosome is defined as the modification of high-mannose N-glycans by this very enzyme followed by uncovering of mannose-6-P; gnptab catalyses the first step. Reason: The term's definition names the enzyme; PAINT node PTN002779133 placement is sound and zebrafish morphants lose mannose phosphorylation of lysosomal glycosidases [PMID:19834066], which wild-type mRNA restores [PMID:23733939]. Core process. Supporting Evidence: PMID:19834066 Decreased mannose phosphorylation of several lysosomal glycosidases was observed in morphant lysates, consistent with the reduction in phosphotransferase activity. PMID:23733939 coinjection of WT GlcNAc-1-phosphotransferase mRNA with the morpholino rescued the MLII phenotype and restored Ξ²-galactosidase phosphorylation to levels approaching endogenous levels, whereas the K732N mRNA failed to correct these defects |
| GO:0000139 Golgi membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Golgi membrane: the alpha/beta precursor is a Golgi-resident membrane protein (UniProt SUBCELLULAR LOCATION, by similarity to human Q3T906), where it phosphorylates high-mannose N-glycans of lysosomal hydrolases. Reason: UniProtKB-SubCell SL-0134 mapping of the Golgi apparatus membrane location. Both alpha and beta subunits are annotated as single-pass Golgi membrane proteins by similarity; the Golgi is where M6P tagging of hydrolases occurs [PMID:26404503]. Accepted as core location. Supporting Evidence: file:DANRE/gnptab/gnptab-uniprot.txt Golgi apparatus membrane PMID:26404503 The Golgi-localized enzyme UDP-GlcNAc: lysosomal enzyme GlcNAc-1-phosphotransferase initiates the synthesis of M6P tags on the hydrolases. |
| GO:0003976 UDP-N-acetylglucosamine-lysosomal-enzyme N-acetylglucosaminephosphotransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Rhea:13581/EC 2.7.8.17 mapping of the transfer of GlcNAc-1-phosphate from UDP-GlcNAc to mannose residues of lysosomal-enzyme N-glycans. Reason: The EC/Rhea-derived term is exactly the reaction in the UniProt CATALYTIC ACTIVITY line and is confirmed experimentally for the zebrafish enzyme [PMID:19834066, PMID:23733939]. Core molecular function. Supporting Evidence: file:DANRE/gnptab/gnptab-uniprot.txt EC=2.7.8.17 PMID:19834066 Decreased mannose phosphorylation of several lysosomal glycosidases was observed in morphant lysates, consistent with the reduction in phosphotransferase activity. |
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Calcium ion binding inferred from the InterPro EF-hand signature (IPR002048); UniProt annotates a single EF-hand region by similarity but no calcium-binding function has been shown for the zebrafish or the human enzyme. Reason: The mapping rests only on an EF-hand motif; the enzyme's characterised activity is the divalent-cation-dependent phosphotransfer (UniProt CATALYTIC ACTIVITY), and none of the cached zebrafish papers assays calcium binding [PMID:19834066, PMID:23733939, PMID:25505245]. Not demonstrably wrong, but an over-interpretation of a domain signature, so marked over-annotated rather than removed. Supporting Evidence: file:DANRE/gnptab/gnptab-uniprot.txt /note="EF-hand" file:DANRE/gnptab/gnptab-uniprot.txt EC=2.7.8.17 file:DANRE/gnptab/gnptab-deep-research-falcon.md GNPTAB contains a multipart **catalytic domain** plus accessory modules including **DMAP1-binding-like domain**, **Notch/EGF-like repeats**, **immunoglobulin-like domain**, **RRM-like/N-terminal modules**, and an **EF-hand Ca2+-binding domain**; these accessory regions contribute to selective hydrolase recognition. |
| GO:0015031 protein transport | IEA GO_REF:0000117 | MODIFY | Summary: Protein transport (ARBA rule ARBA00026546). Gnptab does not move proteins; it generates the M6P recognition marker that M6P receptors later read to sort hydrolases to lysosomes. Reason: GO:0015031 is an ancestor of GO:0016256 (QuickGO ancestor query), so the claim is not false, but the specific term that names the enzyme's own contribution - N-glycan processing to lysosome - is already annotated (IBA, IMP, ISS). Replace the generic ARBA term with GO:0016256 rather than keep a redundant, uninformative parent. Proposed replacements: N-glycan processing to lysosome Supporting Evidence: file:DANRE/gnptab/gnptab-uniprot.txt Catalyzes the formation of mannose 6-phosphate (M6P) markers on high mannose type oligosaccharides in the Golgi apparatus. PMID:25505245 GlcNAc-1-phosphotransferase tags newly synthesized lysosomal enzymes with mannose 6-phosphate recognition markers, which are required for their targeting to the endolysosomal system. |
| GO:0016772 transferase activity, transferring phosphorus-containing groups | IEA GO_REF:0000002 | MODIFY | Summary: Broad parent term (phosphorus-group transferase) from the Stealth CR2 InterPro signature (IPR021520). Reason: The InterPro family mapping is correct but uninformative: the specific child GO:0003976 is supported by EC 2.7.8.17, the UniProt catalytic reaction and zebrafish loss/rescue data [PMID:19834066, PMID:23733939]. Modify to the specific activity. Proposed replacements: UDP-N-acetylglucosamine-lysosomal-enzyme N-acetylglucosaminephosphotransferase activity Supporting Evidence: file:DANRE/gnptab/gnptab-uniprot.txt EC=2.7.8.17 PMID:19834066 Decreased mannose phosphorylation of several lysosomal glycosidases was observed in morphant lysates, consistent with the reduction in phosphotransferase activity. |
| GO:0000139 Golgi membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Golgi membrane: the alpha/beta precursor is a Golgi-resident membrane protein (UniProt SUBCELLULAR LOCATION, by similarity to human Q3T906), where it phosphorylates high-mannose N-glycans of lysosomal hydrolases. Reason: Transferred from human GNPTAB (Q3T906), whose Golgi localization underlies the UniProt SUBCELLULAR LOCATION line; the zebrafish enzyme acts on hydrolases transiting the Golgi [PMID:26404503]. Accepted as core location. Supporting Evidence: file:DANRE/gnptab/gnptab-uniprot.txt Golgi apparatus membrane PMID:26404503 The Golgi-localized enzyme UDP-GlcNAc: lysosomal enzyme GlcNAc-1-phosphotransferase initiates the synthesis of M6P tags on the hydrolases. |
| GO:0003976 UDP-N-acetylglucosamine-lysosomal-enzyme N-acetylglucosaminephosphotransferase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Manual transfer of the phosphotransferase activity from human GNPTAB (Q3T906). Reason: The transferred activity is corroborated directly in zebrafish: loss of phosphotransferase activity in gnptab morphants [PMID:19834066] and mRNA rescue of beta-galactosidase phosphorylation [PMID:23733939]. Core molecular function; the ISS adds nothing beyond the IMP rows but is correct. Supporting Evidence: file:DANRE/gnptab/gnptab-uniprot.txt EC=2.7.8.17 PMID:23733939 coinjection of WT GlcNAc-1-phosphotransferase mRNA with the morpholino rescued the MLII phenotype and restored Ξ²-galactosidase phosphorylation to levels approaching endogenous levels, whereas the K732N mRNA failed to correct these defects |
| GO:0003007 heart morphogenesis | IMP PMID:33055423 Inappropriate cathepsin K secretion promotes its enzymatic a... | KEEP AS NON CORE | Summary: Heart morphogenesis from TALEN gnptab-null (and morphant) embryos: cardiac edema with myocardial and atrioventricular-valve defects [PMID:33055423]. Reason: Full text cached. The heart phenotype is real and rescued by cathepsin K inhibition or ctsk knockdown, which pins the mechanism on mis-secreted cathepsin K rather than on any cardiac activity of gnptab. Under the participation test the gene product does no work in this developmental process: it phosphorylates hydrolase N-glycans in the Golgi, and the phenotype arises because mis-sorted, extracellularly active cathepsin K perturbs TGF-beta-family signalling in the tissue. Kept as non-core (acts_upstream_of_or_within), not removed, because the ZFIN phenotype evidence is genuine. Supporting Evidence: PMID:33055423 gnptabβ/β embryos exhibit pronounced cardiac edema resulting from deficits in both myocardial development and atrioventricular (AV) valve formation. PMID:33055423 Importantly, cathepsin K inhibition restored normal heart and valve development in MLII embryos. |
| GO:0051216 cartilage development | IMP PMID:26404503 Cathepsin-Mediated Alterations in TGFΓ-Related Signaling Und... | KEEP AS NON CORE | Summary: Cartilage development from gnptab morphants: altered chondrocyte maturation with sustained col2a1/sox9a expression, restored by wild-type gnptab mRNA [PMID:26404503]. Reason: Full text cached. The cartilage phenotype is downstream of extracellular cathepsin K activity that disrupts TGF-beta-related Smad signalling; ctsk knockdown restores col2a1a expression. Under the participation test the gene product does no work in this developmental process: it phosphorylates hydrolase N-glycans in the Golgi, and the phenotype arises because mis-sorted, extracellularly active cathepsin K perturbs TGF-beta-family signalling in the tissue. Kept as non-core (acts_upstream_of_or_within), not removed, because the ZFIN phenotype evidence is genuine. Supporting Evidence: PMID:26404503 Here we link extracellular cathepsin K activity to abnormal bone and cartilage development in MLII animals by demonstrating that it disrupts the balance of TGFΓ-related signaling during chondrogenesis. PMID:26404503 Co-injection with the ctsk MO restored WT col2a1a expression levels in 64.5% of the embryos |
| GO:0051216 cartilage development | IGI PMID:26404503 Cathepsin-Mediated Alterations in TGFΓ-Related Signaling Und... | KEEP AS NON CORE | Summary: Genetic interaction with ctsk (ZFIN:ZDB-GENE-001205-4): co-injection of the ctsk morpholino into gnptab morphants restores cartilage marker expression and morphology [PMID:26404503]. Reason: Full text cached. The interaction shows that the cartilage defect of gnptab loss is executed by cathepsin K; gnptab's own role is upstream (keeping Ctsk lysosomal via M6P tagging). Under the participation test the gene product does no work in this developmental process: it phosphorylates hydrolase N-glycans in the Golgi, and the phenotype arises because mis-sorted, extracellularly active cathepsin K perturbs TGF-beta-family signalling in the tissue. Kept as non-core (acts_upstream_of_or_within), not removed, because the ZFIN phenotype evidence is genuine. Supporting Evidence: PMID:26404503 Co-injection with the ctsk MO restored WT col2a1a expression levels in 64.5% of the embryos PMID:26404503 Here we link extracellular cathepsin K activity to abnormal bone and cartilage development in MLII animals by demonstrating that it disrupts the balance of TGFΓ-related signaling during chondrogenesis. |
| GO:0060348 bone development | IMP PMID:26404503 Cathepsin-Mediated Alterations in TGFΓ-Related Signaling Und... | KEEP AS NON CORE | Summary: Bone development from gnptab morphants: reduced osteoblast maturation with imbalanced Sox9/Osx and Smad signalling [PMID:26404503]. Reason: Full text cached; the paper reports that loss of gnptab alters osteoblast maturation via cathepsin K-driven changes in TGF-beta/BMP signalling. Under the participation test the gene product does no work in this developmental process: it phosphorylates hydrolase N-glycans in the Golgi, and the phenotype arises because mis-sorted, extracellularly active cathepsin K perturbs TGF-beta-family signalling in the tissue. Kept as non-core (acts_upstream_of_or_within), not removed, because the ZFIN phenotype evidence is genuine. Supporting Evidence: PMID:26404503 Loss of gnptab expression alters osteoblast maturation PMID:26404503 Here we link extracellular cathepsin K activity to abnormal bone and cartilage development in MLII animals by demonstrating that it disrupts the balance of TGFΓ-related signaling during chondrogenesis. |
| GO:0060348 bone development | IGI PMID:26404503 Cathepsin-Mediated Alterations in TGFΓ-Related Signaling Und... | KEEP AS NON CORE | Summary: Genetic interaction with ctsk (ZFIN:ZDB-GENE-001205-4) for the bone phenotype of gnptab morphants [PMID:26404503]. Reason: Full text cached; ctsk inhibition restores TGF-beta/BMP-related signalling and differentiation markers, identifying cathepsin K as the effector of the skeletal phenotype. Under the participation test the gene product does no work in this developmental process: it phosphorylates hydrolase N-glycans in the Golgi, and the phenotype arises because mis-sorted, extracellularly active cathepsin K perturbs TGF-beta-family signalling in the tissue. Kept as non-core (acts_upstream_of_or_within), not removed, because the ZFIN phenotype evidence is genuine. Supporting Evidence: PMID:26404503 Here we link extracellular cathepsin K activity to abnormal bone and cartilage development in MLII animals by demonstrating that it disrupts the balance of TGFΓ-related signaling during chondrogenesis. PMID:26404503 Loss of gnptab expression alters osteoblast maturation |
| GO:0051216 cartilage development | IMP PMID:25505245 Analysis of mucolipidosis II/III GNPTAB missense mutations i... | KEEP AS NON CORE | Summary: Cartilage development phenotype from GNPTAB-deficient zebrafish used as the rescue background for patient missense alleles [PMID:25505245]. Reason: Abstract only in the cache; the paper uses the morphant craniofacial/cartilage phenotype as the in vivo readout for mutant GNPTAB function. Under the participation test the gene product does no work in this developmental process: it phosphorylates hydrolase N-glycans in the Golgi, and the phenotype arises because mis-sorted, extracellularly active cathepsin K perturbs TGF-beta-family signalling in the tissue. Kept as non-core (acts_upstream_of_or_within), not removed, because the ZFIN phenotype evidence is genuine. Supporting Evidence: PMID:25505245 Rescue experiments using mRNA bearing Notch repeat 1 mutations in GNPTAB-deficient zebrafish revealed selective effects on hydrolase recognition that differ from the DMAP mutation. |
| GO:0003976 UDP-N-acetylglucosamine-lysosomal-enzyme N-acetylglucosaminephosphotransferase activity | IMP PMID:25505245 Analysis of mucolipidosis II/III GNPTAB missense mutations i... | ACCEPT | Summary: IMP from mRNA-rescue of GNPTAB-deficient zebrafish with patient missense alleles, mapping domains required for catalysis and hydrolase recognition. Reason: The abstract (full text not cached) states that rescue experiments with mutant GNPTAB mRNAs in GNPTAB-deficient zebrafish revealed selective effects on hydrolase recognition; this is a direct in vivo assay of the enzyme's activity toward lysosomal hydrolases. Core molecular function; deferring to ZFIN for the assay details. Supporting Evidence: PMID:25505245 GlcNAc-1-phosphotransferase tags newly synthesized lysosomal enzymes with mannose 6-phosphate recognition markers, which are required for their targeting to the endolysosomal system. PMID:25505245 Rescue experiments using mRNA bearing Notch repeat 1 mutations in GNPTAB-deficient zebrafish revealed selective effects on hydrolase recognition that differ from the DMAP mutation. |
| GO:0016256 N-glycan processing to lysosome | IMP PMID:25505245 Analysis of mucolipidosis II/III GNPTAB missense mutations i... | ACCEPT | Summary: N-glycan processing to lysosome is defined as the modification of high-mannose N-glycans by this very enzyme followed by uncovering of mannose-6-P; gnptab catalyses the first step. Reason: Abstract-only cache, but the abstract states that mRNA rescue in GNPTAB-deficient zebrafish revealed selective effects on hydrolase recognition, i.e. the zebrafish enzyme executes the hydrolase-tagging step in vivo. Core process. Supporting Evidence: PMID:25505245 GlcNAc-1-phosphotransferase tags newly synthesized lysosomal enzymes with mannose 6-phosphate recognition markers, which are required for their targeting to the endolysosomal system. PMID:25505245 Rescue experiments using mRNA bearing Notch repeat 1 mutations in GNPTAB-deficient zebrafish revealed selective effects on hydrolase recognition that differ from the DMAP mutation. |
| GO:0016256 N-glycan processing to lysosome | ISS GO_REF:0000024 | ACCEPT | Summary: N-glycan processing to lysosome is defined as the modification of high-mannose N-glycans by this very enzyme followed by uncovering of mannose-6-P; gnptab catalyses the first step. Reason: Transferred from human GNPTAB (Q3T906) and confirmed in zebrafish by loss and rescue of hydrolase mannose phosphorylation [PMID:19834066, PMID:23733939]. Core process. Supporting Evidence: file:DANRE/gnptab/gnptab-uniprot.txt Catalyzes the formation of mannose 6-phosphate (M6P) markers on high mannose type oligosaccharides in the Golgi apparatus. PMID:23733939 coinjection of WT GlcNAc-1-phosphotransferase mRNA with the morpholino rescued the MLII phenotype and restored Ξ²-galactosidase phosphorylation to levels approaching endogenous levels, whereas the K732N mRNA failed to correct these defects |
| GO:0005794 Golgi apparatus | ISS GO_REF:0000024 | ACCEPT | Summary: Golgi apparatus: the alpha/beta precursor is a Golgi-resident membrane protein (UniProt SUBCELLULAR LOCATION, by similarity to human Q3T906), where it phosphorylates high-mannose N-glycans of lysosomal hydrolases. Reason: Transferred from human GNPTAB (Q3T906), whose Golgi localization underlies the UniProt SUBCELLULAR LOCATION line; the zebrafish enzyme acts on hydrolases transiting the Golgi [PMID:26404503]. Accepted as core location. Supporting Evidence: file:DANRE/gnptab/gnptab-uniprot.txt Golgi apparatus membrane PMID:26404503 The Golgi-localized enzyme UDP-GlcNAc: lysosomal enzyme GlcNAc-1-phosphotransferase initiates the synthesis of M6P tags on the hydrolases. |
| GO:0007040 lysosome organization | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Lysosome organization (assembly/arrangement of lysosome constituents). Gnptab supplies the M6P sorting signal through which soluble hydrolases reach the lysosome; without it hydrolases are secreted and lysosomal content is deficient. Reason: Transfer from human GNPTAB (Q3T906) and the zebrafish data both support that gnptab is needed for delivery of lysosomal hydrolase content: gnptab-deficient embryos show reduced hydrolase phosphorylation [PMID:19834066] and mis-secretion/extracellular activity of cathepsin K [PMID:26404503, PMID:33055423]. The enzyme does its work in the Golgi on cargo, however; the direct process is GO:0016256 and lysosome organization is the downstream organellar outcome. Kept as non-core, consistently for IBA and ISS. Supporting Evidence: file:DANRE/gnptab/gnptab-uniprot.txt Catalyzes the formation of mannose 6-phosphate (M6P) markers on high mannose type oligosaccharides in the Golgi apparatus. PMID:33055423 gnptabβ/β embryos exhibit pronounced cardiac edema resulting from deficits in both myocardial development and atrioventricular (AV) valve formation. PMID:26404503 Here we link extracellular cathepsin K activity to abnormal bone and cartilage development in MLII animals by demonstrating that it disrupts the balance of TGFΓ-related signaling during chondrogenesis. |
| GO:0046835 carbohydrate phosphorylation | ISS GO_REF:0000024 | ACCEPT | Summary: Carbohydrate phosphorylation: the reaction places a GlcNAc-1-phosphate on C6 of a mannose residue, i.e. introduces a phosphate onto a carbohydrate (UniProt CATALYTIC ACTIVITY). Reason: Transferred from human GNPTAB (Q3T906); this is the chemistry of the enzyme's own reaction, not a downstream outcome, and it is verified in zebrafish by loss of mannose phosphorylation in morphants [PMID:19834066]. Accepted; it is a chemistry-level description of the same core activity captured by GO:0003976/GO:0016256. Supporting Evidence: file:DANRE/gnptab/gnptab-uniprot.txt EC=2.7.8.17 PMID:19834066 Decreased mannose phosphorylation of several lysosomal glycosidases was observed in morphant lysates, consistent with the reduction in phosphotransferase activity. |
| GO:0003976 UDP-N-acetylglucosamine-lysosomal-enzyme N-acetylglucosaminephosphotransferase activity | IMP PMID:23733939 The DMAP interaction domain of UDP-GlcNAc:lysosomal enzyme N... | ACCEPT | Summary: IMP from morpholino knockdown and mRNA rescue: wild-type gnptab mRNA restores beta-galactosidase phosphorylation in MLII morphants, the K732N DMAP-domain mutant does not. Reason: Full text cached. Rescue of hydrolase phosphorylation by wild-type but not K732N mRNA is direct in vivo evidence that the gene product carries the lysosomal-enzyme-specific GlcNAc-1-phosphotransferase activity. Core molecular function. Supporting Evidence: PMID:23733939 mediates the initial step in the formation of the mannose 6-phosphate recognition signal on lysosomal acid hydrolases PMID:23733939 coinjection of WT GlcNAc-1-phosphotransferase mRNA with the morpholino rescued the MLII phenotype and restored Ξ²-galactosidase phosphorylation to levels approaching endogenous levels, whereas the K732N mRNA failed to correct these defects |
| GO:0048703 embryonic viscerocranium morphogenesis | IMP PMID:23733939 The DMAP interaction domain of UDP-GlcNAc:lysosomal enzyme N... | KEEP AS NON CORE | Summary: Embryonic viscerocranium morphogenesis: the MLII morphant craniofacial phenotype, rescued by wild-type but not K732N gnptab mRNA [PMID:23733939]. Reason: Full text cached. The rescue ties the jaw-cartilage phenotype to the enzyme's hydrolase-phosphorylating activity, but the morphogenetic work is done by chondrocytes and the mis-sorted proteases acting on them. Under the participation test the gene product does no work in this developmental process: it phosphorylates hydrolase N-glycans in the Golgi, and the phenotype arises because mis-sorted, extracellularly active cathepsin K perturbs TGF-beta-family signalling in the tissue. Kept as non-core (acts_upstream_of_or_within), not removed, because the ZFIN phenotype evidence is genuine. Supporting Evidence: PMID:23733939 coinjection of WT GlcNAc-1-phosphotransferase mRNA with the morpholino rescued the MLII phenotype and restored Ξ²-galactosidase phosphorylation to levels approaching endogenous levels, whereas the K732N mRNA failed to correct these defects |
| GO:0002063 chondrocyte development | IMP PMID:19834066 Altered chondrocyte differentiation and extracellular matrix... | KEEP AS NON CORE | Summary: Chondrocyte development from the original morpholino MLII model: accelerated chondrocyte differentiation with mistimed type II collagen and Sox9 expression [PMID:19834066]. Reason: Abstract-only cache, but the abstract itself states the chondrocyte phenotype and its link to reduced phosphotransferase activity. Under the participation test the gene product does no work in this developmental process: it phosphorylates hydrolase N-glycans in the Golgi, and the phenotype arises because mis-sorted, extracellularly active cathepsin K perturbs TGF-beta-family signalling in the tissue. Kept as non-core (acts_upstream_of_or_within), not removed, because the ZFIN phenotype evidence is genuine. Supporting Evidence: PMID:19834066 Investigation of the craniofacial defects in the morphants uncovered striking changes in the timing and localization of both type II collagen and Sox9 expression, suggestive of an accelerated chondrocyte differentiation program. PMID:19834066 Decreased mannose phosphorylation of several lysosomal glycosidases was observed in morphant lysates, consistent with the reduction in phosphotransferase activity. |
| GO:0048701 embryonic cranial skeleton morphogenesis | IMP PMID:19834066 Altered chondrocyte differentiation and extracellular matrix... | KEEP AS NON CORE | Summary: Embryonic cranial skeleton morphogenesis from gnptab morphants: craniofacial defects with misshapen cartilage elements [PMID:19834066]. Reason: Abstract-only cache; the abstract reports craniofacial defects and accumulation of type II collagen within misshapen cartilage elements. Under the participation test the gene product does no work in this developmental process: it phosphorylates hydrolase N-glycans in the Golgi, and the phenotype arises because mis-sorted, extracellularly active cathepsin K perturbs TGF-beta-family signalling in the tissue. Kept as non-core (acts_upstream_of_or_within), not removed, because the ZFIN phenotype evidence is genuine. Supporting Evidence: PMID:19834066 Morphant embryos manifest craniofacial defects, impaired motility, and abnormal otolith and pectoral fin development. PMID:19834066 Investigation of the craniofacial defects in the morphants uncovered striking changes in the timing and localization of both type II collagen and Sox9 expression, suggestive of an accelerated chondrocyte differentiation program. |
| GO:0002063 chondrocyte development | IMP PMID:19834066 Altered chondrocyte differentiation and extracellular matrix... | KEEP AS NON CORE | Summary: Chondrocyte development from the original morpholino MLII model: accelerated chondrocyte differentiation with mistimed type II collagen and Sox9 expression [PMID:19834066]. Reason: Abstract-only cache, but the abstract itself states the chondrocyte phenotype and its link to reduced phosphotransferase activity. Under the participation test the gene product does no work in this developmental process: it phosphorylates hydrolase N-glycans in the Golgi, and the phenotype arises because mis-sorted, extracellularly active cathepsin K perturbs TGF-beta-family signalling in the tissue. Kept as non-core (acts_upstream_of_or_within), not removed, because the ZFIN phenotype evidence is genuine. Supporting Evidence: PMID:19834066 Investigation of the craniofacial defects in the morphants uncovered striking changes in the timing and localization of both type II collagen and Sox9 expression, suggestive of an accelerated chondrocyte differentiation program. PMID:19834066 Decreased mannose phosphorylation of several lysosomal glycosidases was observed in morphant lysates, consistent with the reduction in phosphotransferase activity. |
| GO:0003007 heart morphogenesis | IMP PMID:33055423 Inappropriate cathepsin K secretion promotes its enzymatic a... | KEEP AS NON CORE | Summary: Heart morphogenesis from TALEN gnptab-null (and morphant) embryos: cardiac edema with myocardial and atrioventricular-valve defects [PMID:33055423]. Reason: Full text cached. The heart phenotype is real and rescued by cathepsin K inhibition or ctsk knockdown, which pins the mechanism on mis-secreted cathepsin K rather than on any cardiac activity of gnptab. Under the participation test the gene product does no work in this developmental process: it phosphorylates hydrolase N-glycans in the Golgi, and the phenotype arises because mis-sorted, extracellularly active cathepsin K perturbs TGF-beta-family signalling in the tissue. Kept as non-core (acts_upstream_of_or_within), not removed, because the ZFIN phenotype evidence is genuine. Supporting Evidence: PMID:33055423 gnptabβ/β embryos exhibit pronounced cardiac edema resulting from deficits in both myocardial development and atrioventricular (AV) valve formation. PMID:33055423 Importantly, cathepsin K inhibition restored normal heart and valve development in MLII embryos. |
| GO:0006487 protein N-linked glycosylation | IBA GO_REF:0000033 | ACCEPT | Summary: Protein N-linked glycosylation is an is_a/part_of ancestor of GO:0016256 (verified via QuickGO ancestors); the enzyme adds GlcNAc-1-phosphate to mannose residues of Asn-linked glycans. Reason: PAINT node PTN001171283 places the broad process at a deeper node than the lysosome-specific child; it is correct (the enzyme modifies N-linked glycans of hydrolases [PMID:23733939]) and implied by the accepted GO:0016256 rows. Accepted as a correct broader statement rather than an over-annotation. Supporting Evidence: PMID:23733939 mediates the initial step in the formation of the mannose 6-phosphate recognition signal on lysosomal acid hydrolases file:DANRE/gnptab/gnptab-uniprot.txt EC=2.7.8.17 |
| GO:0007040 lysosome organization | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Lysosome organization (assembly/arrangement of lysosome constituents). Gnptab supplies the M6P sorting signal through which soluble hydrolases reach the lysosome; without it hydrolases are secreted and lysosomal content is deficient. Reason: PAINT (PTN002779133, seeded by human GNPTAB) and the zebrafish data both support that gnptab is needed for delivery of lysosomal hydrolase content: gnptab-deficient embryos show reduced hydrolase phosphorylation [PMID:19834066] and mis-secretion/extracellular activity of cathepsin K [PMID:26404503, PMID:33055423]. The enzyme does its work in the Golgi on cargo, however; the direct process is GO:0016256 and lysosome organization is the downstream organellar outcome. Kept as non-core, consistently for IBA and ISS. Supporting Evidence: file:DANRE/gnptab/gnptab-uniprot.txt Catalyzes the formation of mannose 6-phosphate (M6P) markers on high mannose type oligosaccharides in the Golgi apparatus. PMID:33055423 gnptabβ/β embryos exhibit pronounced cardiac edema resulting from deficits in both myocardial development and atrioventricular (AV) valve formation. PMID:26404503 Here we link extracellular cathepsin K activity to abnormal bone and cartilage development in MLII animals by demonstrating that it disrupts the balance of TGFΓ-related signaling during chondrogenesis. |
| GO:0048701 embryonic cranial skeleton morphogenesis | IMP PMID:19834066 Altered chondrocyte differentiation and extracellular matrix... | KEEP AS NON CORE | Summary: Embryonic cranial skeleton morphogenesis from gnptab morphants: craniofacial defects with misshapen cartilage elements [PMID:19834066]. Reason: Abstract-only cache; the abstract reports craniofacial defects and accumulation of type II collagen within misshapen cartilage elements. Under the participation test the gene product does no work in this developmental process: it phosphorylates hydrolase N-glycans in the Golgi, and the phenotype arises because mis-sorted, extracellularly active cathepsin K perturbs TGF-beta-family signalling in the tissue. Kept as non-core (acts_upstream_of_or_within), not removed, because the ZFIN phenotype evidence is genuine. Supporting Evidence: PMID:19834066 Morphant embryos manifest craniofacial defects, impaired motility, and abnormal otolith and pectoral fin development. PMID:19834066 Investigation of the craniofacial defects in the morphants uncovered striking changes in the timing and localization of both type II collagen and Sox9 expression, suggestive of an accelerated chondrocyte differentiation program. |
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Download this section (compressed HTML)Q: Does zebrafish Gnptab require the gamma subunit (gnptg) for hydrolase recognition in vivo, or can the alpha/beta precursor alone phosphorylate hydrolases in gnptg-deficient embryos?
Q: Is the EF-hand region of Gnptab a functional calcium-binding site, and does calcium modulate phosphotransferase activity?
Experiment: Localise endogenous Gnptab in zebrafish embryos (knock-in tag or validated antibody) with cis-Golgi markers to replace the by-similarity Golgi membrane annotation with direct evidence.
Hypothesis: Zebrafish Gnptab resides in the cis/medial Golgi membrane where hydrolase N-glycans are phosphorylated.
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